Abstract

RATIONALE:

Inhaled beta-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients.

OBJECTIVES:

To screen variants in candidate genes in the steroid and beta-adrenergic pathways for association with response to inhaled beta-agonists.

METHODS:

We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled beta-agonists (bronchodilator response [BDR]) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts.

MEASUREMENTS AND MAIN RESULTS:

We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined P value = 0.00048, adjusted P value = 0.047).

CONCLUSIONS:

These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.

Linkage disequilibrium patterns of ARG1 single nucleotide polymorphisms (SNPs) in the four asthma cohorts. Numbers in the individual blocks represent r2 values for each pair of SNPs (blank values = 100%), with the colors corresponding to D′ values. Plots were created using the program Haploview (http://www.broad.mit.edu/mpg/haploview/).